2026-04-29T07:23:40Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/258132025-12-18T13:00:40Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
Piñeiro-Sabarís, Rebeca
author
MacGrogan, Donal
author
de la Pompa, José Luis
author
Piñeiro-Sabarís, Rebeca
author
MacGrogan, Donal
author
de la Pompa, José Luis
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación La Caixa
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
2024-11-28T18:31:35Z
2024-11-28T18:31:35Z
2024-09-01
Dis Model Mech. 2024 Sep 1;17(9):dmm050934.
https://hdl.handle.net/20.500.12105/25813
39253784
Disease Models & Mechanisms
The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.
eng
ACKR3/CXCR7
Bicuspid aortic valve
Cardiac neural crest
Endocardial cushion development
GATA6
Outflow tract
Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.
review article
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URL
https://repisalud.isciii.es/bitstreams/725a219c-5abe-4c00-bb32-7cadb3fea48c/download
File
MD5
132cf72784fa2b5cc06ff92593b531e6
32635416
application/pdf
Deficient GATA6_CXCR7_Dis Model Mech_2024.pdf